Academic Commons Search Resultshttp://academiccommons.columbia.edu/catalog.rss?f%5Bpub_date_facet%5D%5B%5D=2011&f%5Bsubject_facet%5D%5B%5D=Pharmacology&q=&rows=500&sort=record_creation_date+desc
Academic Commons Search Resultsen-usAging and Pharmacologyhttp://academiccommons.columbia.edu/catalog/ac:176575
Schwartz, Janicehttp://dx.doi.org/10.7916/D8000092Fri, 15 Aug 2014 00:00:00 +0000Learning Objectives: 1. Describe age-related declines in body size, composition, renal elimination, and enzymatic metabolism and how these changes affect medication dosing 2. Recognize the risks of therapy involving multiple medications (polypharmacy) 3. Conceptualize a framework for minimizing polypharmacy 4. Identify unmet needs and knowledge gaps in our medication-based therapies for cardiac conditions of older people.Aging, Medicine, PharmacologyCardiologyPresentationsA Hypothesis Driven Anticancer Path from Cells to Humanshttp://academiccommons.columbia.edu/catalog/ac:144872
Breslow, Ronald C.http://hdl.handle.net/10022/AC:P:12659Tue, 21 Feb 2012 00:00:00 +0000Business, Pharmacologyrb33Chemistry, Engineering and Applied Science, Biological SciencesPresentationsPhosphorylation of TASK-1 and its role in atrial arrhythmiashttp://academiccommons.columbia.edu/catalog/ac:168846
Harleton, Erin RachelTue, 20 Dec 2011 00:00:00 +0000Atrial fibrillation (AF) is the most common sustained arrhythmia in human patients, and is associated with an increased risk of stroke and other morbidity. Acute-onset AF is frequently associated with cardiothoracic surgery, and its initiation is thought to involve proinflammatory signaling. Activated neutrophils are known to be arrhythmogenic, and one of the inflammatory mediators released from neutrophils that contributes to arrhythmogenicity is the phospholipid platelet-activating factor (PAF). PAF acts via a G-protein coupled receptor, present in myocytes, to activate downstream signaling cascades. Data from our lab indicates that inhibition of the two-pore domain potassium channel TASK-1 may contribute to the arrhythmogenic effect of PAF. This study describes the identification of a novel phosphorylation site in the human TASK-1 carboxyl terminus, T383, and has explored the association between phosphorylation at this site and the development or maintenance of various models of atrial fibrillation. Signaling downstream of PAF was previously shown to inhibit the two pore-domain potassium channel TASK-1. This inhibition required the activity of the epsilon isoform of protein kinase C, and a putative phosphorylation site was identified in the murine TASK-1 channel. In this thesis, I have identified a homologous phosphorylation site in the human TASK-1 channel, T383, and have demonstrated that this site is targeted in native atrial myocardium. The known pro-inflammatory effects of PAF, as well as the action potential abnormalities observed in previous studies after direct TASK-1 antagonism in isolated mouse ventricular myocytes, suggested that inhibitory phosphorylation at T383 could play a role in arrhythmias, particularly those with an inflammatory component to their etiology. Therefore, an aim of this thesis was to investigate the relationship between inhibitory TASK-1 phosphorylation and peri-operative atrial fibrillation (POAF) in a canine model. POAF is an acute onset of atrial fibrillation, with a known inflammatory component. This thesis describes the association of POAF with increased infiltration of neutrophils into atrial myocardium and the phosphorylation-dependent inhibition of TASK-1. Furthermore, this thesis has demonstrated that phosphorylation-dependent inhibition of TASK-1 is also associated with sustained atrial fibrillation (AF), in a canine model of chronic AF and in human patients. However, in chronic AF models, phosphorylation at T383 is not responsible for inhibition of the channel, and TASK-1 inhibition is caused by phosphorylation of another as yet unidentified site. Since TASK-1 inhibition is associated with AF in both animal models and in human patients, and in both the acute and chronic disease, TASK-1 could be a new drug target for improved pharmacotherapy in the prevention and treatment of atrial fibrillation.Pharmacology, Physiology, Biologyerh2105Pharmacology, Pharmacology and Molecular SignalingDissertationsFunctional and Biochemical Characterization of KCNQ1/KCNE1 Subunit Interactions in the Cardiac IKs Potassium Channelhttp://academiccommons.columbia.edu/catalog/ac:141922
Chan, Priscilla Jayhttp://hdl.handle.net/10022/AC:P:11793Fri, 11 Nov 2011 00:00:00 +0000The IKs potassium channel, critical to control of heart electrical activity, requires assembly of pore-forming alpha subunits (KCNQ1) and accessory beta (KCNE1) subunits. IKs is the slowly activating component of delayed rectifier K+ current in the heart and is a major contributor to the timing of repolarization of the cardiomyocyte membrane potential. Inherited mutations in either IKs channel subunit are associated with cardiac arrhythmia syndromes, including long QT syndrome (LQTS), short QT syndrome (SQTS) and familial atrial fibrillation (FAF). The biophysical properties of IKs channel current are dramatically altered when KCNE1 associates with the KCNQ1 channel. Functional tetrameric channels can be formed by KCNQ1 alone, but co-assembly with KCNE1 is required for the unique kinetics necessary to regulate human cardiac electrical activity as well as for the channel's functional response to the sympathetic nervous system. Specifically, KCNE1 co-assembly results in a depolarizing shift in the voltage dependence of activation, an increase in the single channel conductance, and an increase in current density. IKs channel current is also characterized by slow activation and deactivation kinetics, with little or no inactivation, in contrast to the KCNQ1 homomeric channel, which is characterized by fast activation and deactivation kinetics and clear inactivation. We wanted to understand how KCNE1 modulates the KCNQ1 channel functionally and investigate the structural determinants of this modulation. In Chapter II, we explore the role(s) of KCNE1 in the context of two KCNQ1 atrial fibrillation associated mutations, S140G and V141M. In contrast to published results, we find distinct dependence on the KCNE1 subunit for V141M, but not for S140G. Having determined the importance of KCNE1 for V141M functionally, we continued to explore the role of KCNE1 structurally for this mutation. Using cysteine substitution in both KCNQ1 and KCNE1 subunits, we monitored spontaneous disulfide bond formation and find that V141C crosslinks to KCNE1, while S140C does not. Having established the functional and structural importance of KCNE1 for V141M, we proposed that there could be mutations in KCNE1 that could reverse the consequences of slow deactivation in the V141M mutation. In Chapter III, we engineer amino terminal KCNE1 mutations and demonstrate that this domain is important for controlling deactivation, but not activation, kinetics of the KCNQ1 channel. We find two KCNE1 mutations, L45F and Y46W, which when co-expressed with either V141M or S140G mutations in KCNQ1, help restore the mutant channel back towards a wild-type IKs channel. From these results, we propose that the amino-terminal domain could play an important role in mediating the rate of deactivation in KCNQ1/KCNE1 channels. After testing mutations on KCNE1 that could affect normal channel function, we continued with a project to study mutations on KCNQ1 that would have similar dramatic effects on the channel. In Chapter IV, we mutated KCNQ1 residue S140 to Threonine and found that S140T co-assembled with KCNE1 produced a channel having functional characteristics opposite to that of S140G/KCNE1 channels. In contrast to S140G/KCNE1 channels, where channels tend to stay open due to very slow deactivation kinetics, S140T/KCNE1 channels tend to be stabilized in the closed state and require more depolarized pulses to open channels. In addition, we find that a mutation at position Y46 in KCNE1, when co-expressed with the S140T mutation in KCNQ1, helps restore the mutant channel back towards a wild-type channel. Again, here we provide evidence that the amino terminal end of KCNE1 could play a role in controlling deactivation. In Chapter V, we investigated the importance of where KCNE1 is located in the channel and also how KCNQ1/KCNE1 subunits assemble using a tandem construct, with 1 KCNE1 subunit tethered to 2 KCNQ1 subunits (EQQ). To investigate the significance of KCNE1 location, we explored the functional consequences of having the S140G or V141M mutations in the proximal (closest to KCNE1) or distal (farthest from KCNE1) KCNQ1 subunit. We find that having a mutation in the proximal subunit is subject to modulation by KCNE1, but not the distal subunit. Using crosslinking, we want to confirm proper assembly of the heterotetrameric channel to verify that KCNE1 assembles between S1 from one KCNQ1 subunit and the S6 domain of an opposing KCNQ1 subunit. Taken together, we demonstrate that the proximity between the N-terminus of KCNE1 and the S1 domain of KCNQ1 could play a role in modulating deactivation kinetics of KCNQ1. These findings will be of great importance in understanding normal IKs channel function, which will be essential for maintaining proper heart function.Pharmacology, Biophysicspjc2111Pharmacology, Pharmacology and Molecular SignalingDissertationsGender Differences in the Subjective Effects of Cocainehttp://academiccommons.columbia.edu/catalog/ac:132417
Laura, Dianahttp://hdl.handle.net/10022/AC:P:10373Mon, 16 May 2011 00:00:00 +0000The literature shows that numerous studies have been done on sex differences in response to drugs of abuse, specifically psychostimulants. Regarding cocaine, significant differences have been found in the initiation of drug use, the development of drug dependence, and treatment-seeking behaviors in men and women. This review strives to summarize these gender-specific differences in cocaine use—including reasons for using, subjective responses while on the drug and the subsequent dependence and treatment—and the role that hormone levels play in this discrepancy. Substantially more studies regarding drug use as a function of sex have been done on rodents. However, differences between the rodent’s 4-day estrous cycle and the human menstrual cycle make it difficult to generalize these results to human populations. It is crucial to examine how much research has been done specifically with male and female humans, taking into account the changing hormone levels throughout the female menstrual cycle, in order to draw conclusions of these gender differences and see what more can be studied. This disparity, and the reasons for it, is extremely important in administering sex-specific treatment in cocaine abuse.Behavioral sciences, Neurosciences, Pharmacologydl2405Psychology (Barnard College), PsychologyUndergraduate theses